Effective mitigation of the pulmonary response to radiation is based on the knowledge of the specific effects of radiation on the various cellular components of the lung and on the context of the exposure. It is clear from the many studies of the pulmonary radiation response that there are two distinct components, radiation pneumonitis, a lymphocytic alveolitis that develops 2 to 3 months after irradiation, and a chronic fibrosis characterized by collagen deposition and scarring. These have been reasonably well characterized in various species and potential targets of mitigation have been identified. What is less well understood is how these processes may be modulated in an environment in which the lung is not the only system that has been damaged. How would the pulmonary inflammatory response be affected when the bone marrow, the source of cells recruited into the lung, has itself been injured? Would processes that enhance bone marrow recovery exacerbate the pulmonary response? Would processes identified as components of the pulmonary response, activation of inflammation, generation of reactive oxygen species (ROS) or vascular leak be somehow affected during multi-organ injury? This is one of the key questions that the current work seeks to address. Radiation exposure during an RDD or IND event is likely to result in damage to multiple system and thus mitigation of any one of them needs to be considered in the context of the other. Equally important is the concept of pulmonary injury being manifested as a result of combined or multiple injury. Does radiation damage to the lung alter the normal pulmonary defense mechanisms so as to exacerbate susceptibility to a secondary insult? Existing information suggests this to be the case. Thus, an important question that we plan to address is whether agents that effectively mitigate radiation pneumonitis and/or fibrosis are effective in restoring this component of pulmonary function. Both of the issues raised above bring to light a number of additional questions including identification of the most effective time to initiate administration of a mitigating agent and its duration of delivery, and best route of administration. We will also consider the feasibility of combining agents to take advantage of synergies that would arise from multiple mitigation targets. Finally, this proposal will continue to explore the question of internal radionuclide contamination and its effects of the lung as well as the potential unique susceptibility to radiation that may exist when exposure occurs in a pediatric population.